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United States Patent |
6,034,055
|
Lockhoff
,   et al.
|
March 7, 2000
|
Glycosyl-amides of 2-aminoacylamino-2-deoxy-sugars
Abstract
The present invention relates to
(2-aminoacylamino-2-deoxy-glycosyl)-amides, which are substituted on the
nitrogen atom of the amino acid, of the general formula (I)
##STR1##
in which the substituents have the meaning given in the description, to
processes for their preparation and to their use in medicaments.
Inventors:
|
Lockhoff; Oswald (Leverkusen, DE);
Mielke; Burkhard (Leverkusen, DE);
Brunner; Helmut (Wuppertal, DE);
Schaller; Klaus (Wuppertal, DE)
|
Assignee:
|
Bayer Aktiengesellschaft (Leverkusen, DE)
|
Appl. No.:
|
255642 |
Filed:
|
February 22, 1999 |
Foreign Application Priority Data
| Aug 30, 1993[DE] | 43 29 095 |
| Feb 11, 1994[DE] | 44 04 371 |
Current U.S. Class: |
514/8; 514/25; 514/885; 536/17.9; 536/18.5 |
Intern'l Class: |
A61K 038/16; A01N 043/04 |
Field of Search: |
514/8,25,885
536/17.9,18.5
424/88,89
|
References Cited
U.S. Patent Documents
4308376 | Dec., 1981 | Lemieux et al.
| |
4362720 | Dec., 1982 | Lemieux et al.
| |
4683222 | Jul., 1987 | Stradler et al.
| |
4855283 | Aug., 1989 | Lockhoff et al.
| |
Foreign Patent Documents |
0 091 645 | Oct., 1983 | EP.
| |
0 338 308 | Oct., 1989 | EP.
| |
Other References
O. Lockhoff et al., Angewandte Chemie International Ed. Eng. vol. 30, pp.
1611-1620 (1991).
A. Huccuch, Kontakte, No. 3, pp. 19-22 (1979).
E.E. Bullesbch, Kontakte, No. 1, pp. 23-35 (1980).
E. Wunsch, in. "Methoden Der Organischen Chemie (Houben-Wegl)",E. Muller,
ed., vol. XV/I and XV/II, 4th ed., thiene Veillog, Stuffgart (1974).
|
Primary Examiner: Wilson; James O.
Attorney, Agent or Firm: Norris, McLaughlin & Marcus, P.A.
Parent Case Text
This application is a divisional of application Ser. No. 08/605,031, filed
on Jun. 25, 1996, now U.S. Pat. No. 5,905,071. This application is a 371
Application of PCT/EP94/02736, filed Aug. 17, 1994.
Claims
We claim:
1. Salts of (2-Aminoacylamino-2-deoxy-glycosyl)-amides substituted by amino
acids, of the formula (I)
##STR8##
in which R.sup.1 represents straight-chain or branched, saturated or
unsaturated alkyl having up to 25 carbon atoms,
R.sup.2 represents straight-chain or branched, saturated or unsaturated
alkyl having up to 25 carbon atoms,
R.sup.3 represents hydrogen, C.sub.1 - to C.sub.7 -alkyl, hydroxy-methyl,
1-hydroxy-ethyl, mercapto-methyl, 2-methylthio-ethyl, 3-amino-propyl,
3-ureido-propyl, 3-guanidyl-propyl, 4-amino-butyl, carboxy-methyl,
carbamoyl-methyl, 2-carboxy-ethyl, 2-carbamoyl-ethyl, benzyl,
4-hydroxy-benzyl, 3-indolyl-methyl or 4-imidazolyl-methyl,
R.sup.4 has the above-mentioned meaning of R.sup.3 and is identical to or
different from R.sup.3,
R.sup.5 represents hydrogen or a protecting group which is customary in
peptide chemistry,
and in which
n denotes a number 1, 2 or 3
and in the case where n=2 or 3 the individual meanings of R.sup.4 are the
same or different.
2. Salts of compounds of the formula (I) according to claim 1, in which
R.sup.1 represents a straight-chain, saturated or monounsaturated alkyl
radical having 10 to 20 carbon atoms,
R.sup.2 represents a straight-chain, saturated or monounsaturated alkyl
radical having 10 to 20 carbon atoms,
R.sup.3 represents hydrogen, C.sub.1 - to C.sub.7 -alkyl, hydroxy-methyl,
1-hydroxy-ethyl, mercapto-methyl, 2-methylthio-ethyl, 3-amino-propyl,
3-ureido-propyl, 3-guanidyl-propyl, 4-amino-butyl, carboxy-methyl,
carbamoyl-methyl, 2-carboxy-ethyl, 2-carbamoyl-ethyl, benzyl,
4-hydroxy-benzyl, 3-indolyl-methyl or 4-imidazolyl-methyl,
R.sup.4 has the above-mentioned meaning of R.sup.5 and is identical to or
different from R.sup.3,
R.sup.5 represents hydrogen, acetyl, benzoyl, trichloroacetyl,
trifluoroacetyl, methoxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl,
trichloroethoxycarbonyl, benzyloxycarbonyl or fluorenylmethoxycarbonyl,
and in which
n denotes a number 1, 2 or 3,
and in the case where n=2 or 3 the individual meanings of R.sup.4 are the
same or different.
3. A method of stimulating the immune system of a human or animal which
comprises administering to such human or animal an amount effective
thereof of a salt according to claim 1.
4. A composition for stimulating the immune system of a human or animal
comprising a salt according to claim 1 and a pharmaceutically acceptable
carrier.
Description
The invention relates to (2-aminoacylamino-2-deoxy-glycosyl)-amides which
are substituted on the nitrogen atom, to processes for their preparation,
and their use in medicaments.
It is known that glycosylamides of aldopyranoses or of amino sugars are
able to intensify the endogenous immune response (DE-A 32 13 650). It is
also known that (2-amino-2-deoxy-glycosyl)-amides substituted with amino
acids can bring about an increase both in the specific and in the
nonspecific immune response (DE-A 35 21 994).
Now, the present invention relates to
(2-aminoacylamino-2-deoxy-glycosyl)-amides which are substituted on the
nitrogen atom of the amino acid, of the general formula (I).
##STR2##
in which R.sup.1 represents straight-chain or branched, saturated or
unsaturated alkyl having up to 25 carbon atoms,
R.sup.2 represents straight-chain or branched, saturated or unsaturated
alkyl having up to 25 carbon atoms,
R.sup.3 represents hydrogen, C.sub.1 - to C.sub.7 -alkyl, hydroxy-methyl,
1-hydroxy-ethyl, mercapto-methyl, 2-methylthio-ethyl, 3-amino-propyl,
3-ureido-propyl, 3-guanidyl-propyl, 4-amino-butyl, carboxy-methyl,
carbamoyl-methyl, 2-carboxy-ethyl, 2-carbamoyl-ethyl, benzyl,
4-hydroxy-benzyl, 3-indolyl-methyl or 4-imidazolyl-methyl,
R.sup.4 has the above-indicated meaning of R.sup.3 and is identical to or
different from it,
R.sup.5 represents hydrogen or a protecting group which is customary in
peptide chemistry (cf. A. Hubbuch, Kontakte (Darmstadt) 1979, 14; E. E.
Bullesbach, Kontakte (Darmstadt) 1980, 23),
and in which
n denotes a number 1, 2 or 3,
and in the case where n=2 or 3 the individual meanings of R.sup.4 can be
different.
The compounds according to the invention have a plurality of asymmetric
carbon atoms. They can therefore exist in different stereochemical forms.
The invention relates both to the individual isomers and to mixtures
thereof.
Preferred compounds of the general formula (I) are those in which
R.sup.1 represents a straight-chain, saturated or monounsaturated alkyl
radical having 10 to 20 carbon atoms,
R.sup.2 represents a straight-chain, saturated or monounsaturated alkyl
radical having 10 to 20 carbon atoms,
R.sup.3 represents hydrogen, C.sub.1 - to C.sub.7 -alkyl, hydroxy-methyl,
1-hydroxy-ethyl, mercapto-methyl, 2-methylthio-ethyl, 3-amino-propyl,
3-ureido-propyl, 3-guanidyl-propyl, 4-amino-butyl, carboxyl-methyl,
carbamoyl-methyl, 2-carboxy-ethyl, 2-carbamoyl-ethyl, benzyl,
4-hydroxy-benzyl, 3-indolyl-methyl or 4-imidazolyl-methyl,
R.sup.4 has the above-indicated meaning of R.sup.3 and is identical to or
different from it,
R.sup.5 represents hydrogen, acetyl, benzoyl, trichloroacetyl,
trifluoroacetyl, methoxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl,
trichloroethoxycarbonyl, benzyloxycarbonyl or fluorenylmethoxycarbonyl,
and in which
n denotes a number 1, 2 or 3,
and in the case where n=2 or 3 the individual meanings of R.sup.4 can be
different.
In addition, two processes have been found for the preparation of the
compounds of the general formula (I) according to the invention. The two
processes differ in the sequence and in the structural units with which
the peptide linkages can be linked.
In the first process (A),
N-(2-aminoacylamino-2-deoxy-hexopyranosyl)-N-alkyl-carboxamides of the
formula (II)
##STR3##
in which R.sup.1, R.sup.2 and R.sup.3 have the meaning given above are
reacted with amino acid derivatives or di- or tripeptide derivatives of
the general formula (III)
##STR4##
in which R.sup.4 has the meaning give above,
R.sup.6 represents a protecting group, customary in peptide chemistry, for
the nitrogen atom of amino acids, which can b eliminated again selectively
to give the peptide linkage, and
R.sup.7 represents a hydroxyl group or a leaving group, customary in
peptide chemistry, for the activation of amino acids,
n denotes a number 1, 2 and 3,
and in the case where n is 2 or 3 the individual meanings of R.sup.4 can be
different, with one another in such a way that an amide linkage is formed
and compounds of the general formula (I) are obtained.
In a second reaction step, the N-terminal protecting group R.sup.5 in the
compounds of the formula (I) is eliminated to give the compounds of the
general formula (I) having a free amino group.
The starting compounds of the general formula (II) are known and can be
prepared by the methods described in DE 3521994 (Le A 23620).
The derivatives of the di- or tripeptides of the general formula (III) are
likewise known in principle.
Examples of suitable protecting groups R.sup.6 for the amino function in
compounds of the formula (III) are acyl groups such as trifluoroacetyl or
trichloroacetyl, o-nitrophenylsulphenyl, 2,4-dinitrophenylsulphenyl or
optionally substituted lower alkoxycarbonyl, for example methoxycarbonyl,
tert-butyloxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl,
fluorenylmethoxycarbonyl or 2,2,2-trichloroethoxycarbonyl.
Preferred amino-protecting groups R.sup.6 are the tert-butyloxycarbonyl
group or the benzyloxycarbonyl group.
The linkage of the 2-aminoacylamino-2-deoxy-glycosylamides of the general
formula (II) with the N-substituted amino acids, di- or tripeptides of the
general formula (III) can be accomplished by conventional methods of
peptide chemistry (E. Wunsch et al.: Synthese von Peptiden [Synthesis of
Peptides] in: Methoden der Organischen Chemie [Methods of Organic
Chemistry] (Houben-Weyl) (E. Muller, ed.) Volume XV/I and XV/II, 4th ed.,
Thieme Verlag Stuttgart (1974)).
Conventional methods are, for example, the condensation of the amino
function in the compound of the general formula (II) with an N-protected
amino-acid or peptide derivative of the general formula (III) in the
presence of dehydrating agents, for example carbodiimides such as
dicyclohexylcarbodiimide or diisopropylcarbodiimide.
The condensation of the compounds of the formula (II) with the compounds of
the formula (III) can also be carried out if the carboxyl group is
activated. An activated carboxyl group can, for example, be a carboxylic
anhydride, preferably a mixed anhydride with alkyl carbonates, acetic acid
or another carboxylic acid, or an amide of the acid, such as an
imidazolide, or an activated ester, for example the cyanomethyl ester,
pentachlorophenyl ester or N-hydroxyphthalimide ester. Activated esters
can also be obtained from the amino-acid derivatives of the formula (III)
in which R.sup.7 represents OH, and N-hydroxysuccinimide or
1-hydroxybenzotriazole in the presence of a dehydrating agent such as
carbodiimide.
In the second process step for the preparation of the compounds of the
general formula (I), the protecting group R.sup.5 is eliminated.
The protecting groups R.sup.5 which are preferably used in the compounds of
the general formula (I), the N-carbobenzoxy group and the
N-tert-butyloxycarbonyl group, can be eliminated to give the amide groups
which exist in the compounds. Methods of this type are known in principle.
The carbobenzoxy group in the compounds of the formula (I) can be
selectively eliminated by hydrogenolysis in the presence of transition
metals, for example palladium on carbon, in a suitable solvent such as,
for example, methanol, ethanol, glacial acetic acid or tetrahydrofuran,
either in pure form or in a combination of the solvents with one another,
or alternatively with water, it being possible to operate both at
atmospheric pressure and at elevated pressure.
The tert-butoxycarbonyl group in the compounds of the formula (I) can be
eliminated by means of acidolytic processes. Examples of suitable
conditions are the use of hydrogen chloride or trifluoroacetic acid,
either in pure form or diluted in suitable solvents such as, for example,
glacial acetic acid, dichloromethane, diethyl ether, dioxane or ethyl
acetate.
The compounds of the general formula (I) obtained in this way are isolated,
by methods which are known per se, in the form of crystalline or amorphous
solids and are purified if necessary by recrystallization, chromatography,
extraction, etc.
In the second process (B), the compounds of the formula (I) according to
the invention are obtained by linking
N-(2-amino-2-deoxy-hexopyranosyl)-N-alkyl-carboxamides with di-, tri- or
tetrapeptide derivatives.
Process (B) is characterized in that compounds of the general formula (IV)
##STR5##
in which R.sup.1 and R.sup.2 have the meaning given above are reacted with
derivatives of di-, tri- or tetrapeptides of the general formula (III)
##STR6##
in which R.sup.4 and R.sup.7 have the meaning given above and
R.sup.6 denotes a protecting group
and in which
n denotes a number 2, 3 or 4
with one another under the abovementioned conditions with formation of a
peptide linkage, to give the compounds of the formula (V)
##STR7##
in which R.sup.1, R.sup.2, R.sup.4 and R.sup.6 have the meanings given
above and
n denotes a number 2, 3 or 4,
which are substituted on the N-terminal amino group.
Subsequently, in the substituted compounds of the formula (V), the
amino-protecting groups R.sup.6 must be eliminated to give compounds
having an unsubstituted amino group, of the general formula (I).
The preparation of the starting compounds of the formula (IV) is described
in DE 3521994 (Le A 23620). For the conditions of the linking of the
peptide linkages, the general methods of peptide synthesis indicated above
can be employed.
Also part of the invention are salts of the compounds of the formula (I).
These are primarily customary, pharmaceutically utilizable, nontoxic
salts, for example the ammonium salts of chlorides, acetates, lactates.
It has been found that the compounds of the general formula (I) identified
more closely below bring about a stimulation of and therefore an
improvement in endogenous defence processes. The compounds can therefore
be used as immunologically active medicaments. The immunostimulating
effect has been demonstrated both in vivo in animal experimentation and in
vitro on cells of the defence system. This fact is evidenced by the
following experimental results.
Female mice (CFW.sub.1) weighing about 18 g were divided into groups on the
basis of random criteria. The animals were then administered,
intraperitoneally, subcutaneously or intravenously, a dose of 10 mg/kg of
body weight of the compounds of the formula (I) according to the
invention, or received physiological saline solution. Twenty-four hours
later, the animals were injected intraperitoneally with 10 times the
lethal dose (LD.sub.50) of Escherichia coli C14. The table which follows
shows that the survival rates seven days after infection in mice which had
been treated with the compounds of the formula (I) according to the
invention was significantly greater than that of mice having received
physiological saline solution.
TABLE
______________________________________
Surviving mice on day 7 p.i.
Example (difference relative to control)
p*
______________________________________
22a 7/16 (44%) <0.05
22b 7/16 (44%) <0.05
22c 9/16 (56%) <0.01
22d 12/16 (75%) <0.001
22e 9/16 (56%) <0.01
22h 10/16 (63%) <0.001
22k 11/16 (69%) <0.001
25f 4/12 (33%)
26a 10/16 (63%) <0.001
26b 11/16 (69%) <0.001
26c 9/16 (56%) <0.01
26d 7/16 (44%) <0.05
26e 11/16 (69%) <0.001
26f 7/16 (44%) <0.05
26g 10/16 (63%) <0.001
26h 9/16 (56%) <0.01
26i 14/16 (88%) <0.001
26j 11/16 (69%) <0.001
26k 10/16 (63%) <0.001
27c 4/16 (25%)
27d 12/16 (75%) <0.001
27e 7/16 (44%) <0.05
27h 8/16 (50%) <0.01
27i 7/16 (44%) <0.05
27j 8/16 (50%) <0.01
______________________________________
*Fisher test
p.i. = postinfection
Protective screening in the neutropenic Candida infection model
The aim of this experimental model is to discover substances which
stimulate endogenous defence in neutropenic mice.
Methodology
At time -96 h, the mice are treated intraperitoneally with 0.2 ml of
Endoxan in a dose of 200 mg/kg per animal. At the times -72, -48 and -24
h, the mice are treated intraperitoneally with 0.2 ml of the solution of
the screening substance. Alternatively, treatments with screening
substances are also carried out with 0.2 ml of solution subcutaneously and
intravenously, and with 0.5 ml of solution orally. 2 groups each
containing 10 animals are used per preparation. Routinely, one group is
treated with 10 mg/kg, the other with 30 mg/kg, of body weight. For
in-depth examinations, substantially lower dosages are also used.
At time 0 h, the mice are infected intravenously with 0.2 ml of a lethal
pathogen suspension into the caudate vein.
Observation and assessment
The mice are observed up to 4 h after treatment in order to enable
detection of any instances of incompatibility with the preparation.
From 1 day to 14 days after infection, the mice are assessed once daily
before midday. The state of health is registered in 5 grades.
(--good--slightly ill--ill--severely ill--dead--) The severely ill mice
are killed after evaluation so as not to suffer.
Result
The result documented is the survival ratio and/or retardation of the
clinical picture. In both cases this is done in comparison with the
control mice treated with Endoxan.
Techniques
Intraperitoneal, subcutaneous and intravenous administrations were carried
out by us using a 1 ml disposable syringe and a No. 18 syringe. Oral
administration is carried out with a 5 ml disposable syringe and the No.
12 syringe with olive. For intraperitoneal and oral administration, the
mice are fixed in the hand. In the case of subcutaneous administration,
the mice are fixed on the case lid. In the case of intravenous
administration and intravenous infection, the mice are fixed in a mouse
enforcement cage. In addition, prior to intravenous treatment and
intravenous infection the mice are placed for about 10 minutes under red
light in order to widen the caudate veins.
Parameters
Mouse: B.sub.6 D.sub.2 F.sub.1 20 g, female
Pathogen: Candida albicans, 5.times.10.sup.5 microbes per mouse
Substance: Endoxan is water-soluble. The screening substances, if possible,
are likewise dissolved in sterile water. Where this is not possible, an
attempt is made to dissolve them as follows: initial dissolution in pure
DMSO (final concentration of DMSO in the solution for administration=2%).
Cremophor was then added (final concentration of Cremophor in the solution
for administration=8%). The composition is made up with sterile water to
the final volume.
Living conditions: The animals are kept in type II Makrolon cages. All
animals receive feed and water ad libitum.
The compound from Example 22h shows a good protective effect in the Candida
infection model.
PREPARATION EXAMPLES
Example 1
General procedure for reacting the 2-amino-2-deoxy compounds of the formula
(IV) and the 2-aminoacylamino-2-deoxy compounds of the formula (II) with
N-protected amino acids, di- or tripeptides of the general formula (III)
to give the N-protected 2-aminoacylamino-2-deoxy compounds, substituted
with amino acids, of the formula (I):
N,N'-Dicyclohexylcarbodiimide (1.88 g, 8.4 mmol) is added to a mixture of
the N-protected .alpha.-amino acid or, respectively, of the di- or
oligopeptide (7.7 mmol), N-hydroxysuccinimide (1.77 g, 15.4 mmol) and
N,N-dimethylformamide (70 ml), and the mixture is stirred at 20.degree.
for 30 min. Ethyl-diisopropylamine (8.0 mmol) and the 6-amino-6-deoxy
compound of Example II (7.0 mmol) are added, and stirring is continued for
16 h. Water (3 ml) is added to the mixture, stirring is continued for 30
minutes, and the mixture is concentrated under reduced pressure to a
syrup. The residue is stirred with diethyl ether (100 ml), the
precipitated urea is filtered off with suction, and the filtrate is
concentrated under a high vacuum. The residue is taken up in diethyl ether
(150 ml), washed three times with water (70 ml each time), dried over
magnesium sulphate and concentrated under reduced pressure to a syrup. The
residue is filtered over silica gel (eluent dichloromethane/methanol/conc.
ammonia water 25:1:0.05).
11a
N-[2(N-Carbobenzoxy-glycyl-glycyl)-amino-2-deoxy-.beta.-D-glucopyranosyl]-
N-dodecyl-dodecanamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-dodecyl-dodecanamide
and N-carbobenzoxy-glycine.
11b
N-[2-(N-Carbobenzoxy-L-alanyl-glycyl)-amino-2-deoxy-.beta.-D-glucopyranosy
l]-N-dodecyl-dodecanamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-dodecyl-dodecanamide
and N-carbobenzoxy-L-alanine.
11c
N-[2-(N-Carbobenzoxy-L-phenylalanyl-glycyl)-amino-2-deoxy-.beta.-D-glucopy
ranosyl]-N-dodecyl-dodecanamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-dodecyl-dodecanamide
and N-carbobenzoxy-L-phenylalanine. Yield 53%. R.sub.f 0.29
(dichloromethane/methanol/conc. ammonia 15:1:0.1).
11d
N-[2-(N-Carbobenzoxy-glycyl-L-alanyl)-amino-2-deoxy-.beta.-D-glucopyranosy
l]-N-dodecyl-dodecanamide.
from
N-(2-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-dodecyl-dodecanamid
e and N-carbobenzoxy-glycine.
11e
N-[2-(N-Carbobenzoxy-glycyl-D-alanyl)-amino-2-deoxy-.beta.-D-glucopyranosy
l]-N-dodecyl-dodecanamide.
from
N-(2-D-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-dodecyl-dodecanamid
e and N-carbobenzoxy-glycine.
11f
N-[2-(N-Carbobenzoxy-4-O-benzyl-L-aspartyl-D-alanyl)-amino-2-deoxy-.beta.-
D-glucopyranosyl]-N-dodecyl-dodecanamide.
from
N-(2D-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-dodecyl-dodecanamide
and N-carbobenzoxy-4-O-benzyl-L-aspartic acid. Yield 63%. R.sub.f 0.57
(dichloromethane/methanol/conc. ammonia 15:1:0.1).
12a
N-[2-(N-Carbobenzoxy-glycyl-glycyl)-amino-2-deoxy-.beta.-D-glucopyranosyl]
-N-tetradecyl-dodecanamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-dodecanami
de and N-carbobenzoxy-glycine. Yield 47%. [.alpha.].sub.D =+18.7.degree.
(c=0.95, (dichloromethane). m.p. 108-109.degree..
12b
N-[2-(N-Carbobenzoxy-sarcosyl-glycyl)-amino-2-deoxy-.beta.-D-glucopyranosy
l]-N-tetradecyl-dodecanamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-dodecanami
de and N-carbobenzoxy-sarcosine. Yield 64%. [.alpha.].sub.D =+18.4.degree.
(c=1.02, dichloromethane). m.p. 76-77.degree..
12c
N-[2-(N-Carbobenzoxy-L-alanyl-glycyl)-amino-2-deoxy-.beta.-D-glucopyranosy
l]-N-tetradecyl-dodecanamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-dodecanami
de and N-carbobenzoxy-L-alanine. Yield 94%. [.alpha.].sub.D =+16.3.degree.
(c=1.12, dichloromethane). m.p. 103-105.degree..
12d
N-[2-(N-Carbobenzoxy-L-valyl-glycyl)-amino-2-deoxy-.beta.-D-glucopyranosyl
]-N-tetradecyl-dodecanamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-dodecanami
de and N-carbobenzoxy-L-valine. Yield 76%. [.alpha.].sub.D =+17.8.degree.
(c=1.09, dichloromethane). m.p. 85-86.degree..
12e
N-[2-(N-Carbobenzoxy-L-seryl-glycyl)-amino-2-deoxy-.beta.-D-glucopyranosyl
]-N-tetradecyl-dodecanamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-dodecanami
de and N-carbobenzoxy-L-serine. Yield 76%. [.alpha.].sub.D =+20.3.degree.
(c=0.89, dichloromethane). m.p. 87-89.degree..
12f
N-[2-(N-Carbobenzoxy-O-benzyl-L-glutamyl-glycyl)-amino-2-deoxy-.beta.-D-gl
ucopyranosyl]-N-tetradecyl-dodecanamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-dodecanami
de and N-carbobenzoxy-O-benzyl-L-glutamic acid.
12g
N-[2-(N-Carbobenzoxy-L-glutaminyl-glycyl)-amino-2-deoxy-.beta.-D-glucopyra
nosyl]-N-tetradecyl-dodecanamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-dodecanami
de and N-carbobenzoxy-L-glutamine.
12h
N-[2-(N-Carbobenzoxy-glycyl-glycyl-glycyl)-amino-2-deoxy-.beta.-D-glucopyr
anosyl]-N-tetradecyl-dodecanamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-dodecanami
de and N-carbobenzoxy-glycyl-glycine. Yield 52%. [.alpha.].sub.D
=+14.7.degree. (c=1.01, tetrahydrofuran). m.p., 99-100.degree..
12i
N-[2-(N-Carbobenzoxy-glycyl-glycyl-glycyl-glycyl)-amino-2-deoxy-.beta.-D-g
lucopyranosyl]-N-tetradecyl-dodecanamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-dodecanami
de and N-carbobenzoxy-glycyl-glycyl-glycine.
12j
N-[2-(N-Carbobenzoxy-L-alanyl-glycyl-glycyl)-amino-2-deoxy-.beta.-D-glucop
yranosyl]-N-tetradecyl-dodecanamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-dodecanami
de and N-carbobenzoxy-L-alanyl-glycine.
12k
N-[2-(N-Carbobenzoxy-L-alanyl-L-alanyl-glycyl)-amino-2-deoxy-.beta.-D-gluc
opyranosyl]-N-tetradecyl-dodecanamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-dodecanami
de and N-carbobenzoxy-L-alanyl-L-alanine. Yield 70%. [.alpha.].sub.D
=+10.3.degree. (c=0.92, tetrahydrofuran). m.p. 99-100.degree..
13a
N-[2-(N-Carbobenzoxy-glycyl-glycyl)-amino-2-deoxy-.beta.-D-glucopyranosyl]
-N-octadecyl-dodecanamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-dodecanamid
e and N-carbobenzoxy-glycine.
13b
N-[2-(N-Carbobenzoxy-L-valyl-glycyl)-amino-2-deoxy-.beta.-D-glucopyranosyl
]-N-octadecyl-dodecanamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-dodecanamid
e and N-carbobenzoxy-L-valine.
13c
N-[2-(N-Carbobenzoxy-L-leucyl-glycyl)-amino-2-deoxy-.beta.-D-glucopyranosy
l]-N-octadecyl-dodecanamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-dodecanamid
e and N-carbobenzoxy-L-leucine.
13d
N-[2-N-Carbobenzoxy-O-benzyl-L-glutamyl-glycyl)-amino-2-deoxy-.beta.-D-glu
copyranosyl]-N-octadecyl-dodecanamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-dodecanamid
e and N-carbobenzoxy-O-benzyl-L-glutamic acid.
13e
N-[2-(N-Carbobenzoxy-L-glutaminyl-glycyl)-amino-2-deoxy-.beta.-D-glucopyra
nosyl]-N-octadecyl-dodecanamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-dodecanamid
e and N-carbobenzoxy-L-glutamine.
13f
N-[2-(Tri-N-carbobenzoxy-L-arginyl-glycyl)-amino-2-deoxy-.beta.-D-glucopyr
anosyl]-N-octadecyl-dodecanamide.
from N-(2-glycyl-amino-2-.beta.-D-glucopyranosyl)-N-octadecyl-dodecanamide
and tri-N-carbobenzoxy-L-arginine.
14a
N-[2-(N-Carbobenzoxy-glycyl-glycyl)-amino-2-deoxy-.beta.-D-glucopyranosyl]
-N-tetradecyl-octadecanamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-octadecana
mide and N-carbobenzoxy-glycine.
14b
N-[2-(N-Carbobenzoxy-glycyl-L-alanyl)-amino-2-deoxy-.beta.-D-glucopyranosy
l]-N-tetradecyl-octadecanamide.
from
N-(2-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-octadeca
namide and N-carbobenzoxy-glycine.
14c
N[2-(N-Carbobenzoxy-L-leucyl-L-alanyl)-amino-2-deoxy-.beta.-D-glucopyranos
yl]-N-tetradecyl-octadecanamide.
from
N-(2-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-octadeca
namide and N-carbobenzoxy-L-leucine.
14d
N-[2-(N-Carbobenzoxy-L-alanyl-L-leucyl)-amino-2-deoxy-.beta.-D-glucopyrano
syl]-N-tetradecyl-octadecanamide.
from
N-(2-L-leucyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-octadeca
namide and N-carbobenzoxy-L-alanine.
14e
N-[2-(N-Carbobenzoxy-L-leucyl-L-leucyl)-amino-2-deoxy-.beta.-D-glucopyrano
syl]-N-tetradecyl-octadecanamide.
from
N-(2-L-leucyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-octadeca
namide and N-carbobenzoxy-L-leucine. Yield 61%. R.sub.f 0.50
(dichloromethane/methanol/conc. ammonia 15:1:0.1).
15a
N-[2-(N-Carbobenzoxy-glycyl-glycyl)-amino-2-deoxy-.beta.-D-glucopyranosyl]
-N-octadecyl-octadecanamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-octadecanam
ide and N-carbobenzoxy-glycine.
15b
N-[2-(N-Carbobenzoxy-L-alanyl-L-alanyl)-amino-2-deoxy-.beta.-D-glucopyrano
syl]-N-octadecyl-octadecanamide.
from N-(2-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-octadecanamide
and N-carbobenzoxy-L-alanyl-L-alanine.
15c
N-[2-(N-Carbobenzoxy-D-alanyl-L-alanyl)-amino-2-deoxy-.beta.-D-glucopyrano
syl]-N-octadecyl-octadecanamide.
from N-(2-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-octadecanamide
and N-carbobenzoxy-D-alanyl-L-alanine.
15d
N-[2-(N-Carbobenzoxy-D-alanyl-D-alanyl)-amino-2-deoxy-.beta.-D-glucopyrano
syl]-N-octadecyl-octadecanamide.
from N-(2-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-octadecanamide
and N-carbobenzoxy-D-alanyl-D-alanine.
15e
N-[2-(N-Carbobenzoxy-D-alanyl-L-alanyl)-amino-2-deoxy-.beta.-D-glucopyrano
syl]-N-octadecyl-octadecanamide.
from N-(2-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-octadecanamide
and N-carbobenzoxy-D-alanyl-L-alanine.
15f
N-[2-DI-N-tert-butyloxycarbonyl-L-lysyl-L-alanyl)-amino-2-deoxy-.beta.-D-g
lucopyranosyl]-N-octadecyl-octadecanamide.
from N-(2-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-octadecanamide
and di-N-tert-butyloxycarbonyl-L-lysyl-L-alanine.
16a
N-[2-(N-tert-Butyloxycarbonyl-glycyl-glycyl)-amino-2-deoxy-.beta.-D-glucop
yranosyl]-N-tetradecyl-oleamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-oleamide
and N-tert-butyloxycarbonyl-glycine. Yield 68%. [.alpha.].sub.D
=+14.5.degree. (c=0.92, tetrahydrofuran).
16b
N-[2-(N-tert-Butyloxycarbonyl-L-alanyl-glycyl)-amino-2-deoxy-.beta.-D-gluc
opyranosyl]-N-tetradecyl-oleamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-oleamide
and N-tert-butyloxycarbonyl-L-alanine. Yield 79%. [.alpha.].sub.D
=+12.1.degree. (c=0.87, tetrahydrofuran).
16c
N-[2-(N-tert-Butyloxycarbonyl-glycyl-glycyl-glycyl)-amino-2-deoxy-.beta.-D
-glucopyranosyl]-N-tetradecyl-oleamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-oleamide
and N-tert-butyloxycarbonyl-glycyl-glycine. Yield 74%. [.alpha.].sub.D
=+14.2.degree. (c=1.00, tetrahydrofuran).
16d
N-[2-(N-tert-Butyloxycarbonyl-L-alanyl-L-alanyl-glycyl)-amino-2-deoxy-.bet
a.-D-glucopyranosyl]-N-tetradecyl-oleamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-oleamide
and N-tert-butyloxycarbonyl-L-alanyl-L-alanine. Yield 71%. [.alpha.].sub.D
=+7.4.degree. (c=0.82, tetrahydrofuran).
16e
N-[2-(N-tert-Butyloxycarbonyl-glycyl-L-alanyl)-amino-2-deoxy-.beta.-D-gluc
opyranosyl]-N-tetradecyl-oleamide.
from
N-(2-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-oleamide
and N-tert-butyloxycarbonyl-glycine. Yield 61%. [.alpha.].sub.D 32
+1.2.degree. (c=0.86, tetrahydrofuran).
16f
N-[2-(N-tert-Butyloxycarbonyl-L-alanyl-L-alanyl)-amino-2-deoxy-.beta.-D-gl
ucopyranosyl]-N-tetradecyl-oleamide.
from
N-(2-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-oleamide
and N-tert-butyloxycarbonyl-L-alanine. Yield 59%. [.alpha.].sub.D
=+0.2.degree. (c=0.86, tetrahydrofuran).
16g
N-[2-(N-tert-Butyloxycarbonyl-L-leucyl-L-alanyl)-amino-2-deoxy-.beta.-D-gl
ucopyranosyl]-N-tetradecyl-oleamide.
from
N-(2-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-oleamide
and N-tert-butyloxycarbonyl-L-leucine. Yield 56%. [.alpha.].sub.D
=-2.7.degree. (c=0.86, tetrahydrofuran).
16h
N-[2-(N-tert-Butyloxycarbonyl-glycyl-glycyl-L-alanyl)-amino-2-deoxy-.beta.
-D-glucopyranosyl]-N-tetradecyl-oleamide.
from
N-(2-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-oleamide
and N-tert-butyloxycarbonyl-glycyl-glycine. Yield 56%. [.alpha.].sub.D
=+8.5.degree. (c=0.82, tetrahydrofuran).
16i
N-[2-(N-tert-Butyloxycarbonyl-glycyl-L-leucyl)-amino-2-deoxy-.beta.-D-gluc
opyranosyl]-N-tetradecyl-oleamide.
from
N-(2-L-leucyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-oleamide
and N-tert-butyloxycarbonyl-glycine. Yield 79%. [.alpha.].sub.D
=-1.4.degree. (c=0.87, tetrahydrofuran).
16j
N-[2-(N-tert-Butyloxycarbonyl-L-alanyl-L-leucyl)-amino-2-deoxy-.beta.-D-gl
ucopyranosyl]-N-tetradecyl-oleamide.
from
N-(2-L-leucyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-oleamide
and N-tert-butyloxycarbonyl-L-alanine. Yield 90%. [.alpha.].sub.D
=-8.1.degree. (c=0.98, tetrahydrofuran).
16k
N-[2-(N-tert-Butyloxycarbonyl-glycyl-glycyl-L-leucyl)-amino-2-deoxy-.beta.
-D-glucopyranosyl]-N-tetradecyl-oleamide.
from
N-(2-L-leucyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-oleamide
and N-tert-butyloxycarbonyl-glycyl-glycine. Yield 92%. [.alpha.].sub.D
=+4.2.degree. (c=0.83, tetrahydrofuran).
17a
N-[2-(N-tert-Butyloxycarbonyl-glycyl-glycyl)-amino-2-deoxy-.beta.-D-glucop
yranosyl]-N-octadecyl-oleamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-oleamide an
d N-tert-butyloxycarbonyl-glycine.
17b
N-[2-(N-tert-Butyloxycarbonyl-L-alanyl-glycyl)-amino-2-deoxy-.beta.-D-gluc
opyranosyl]-N-octadecyl-oleamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-oleamide an
d N-tert-butyloxycarbonyl-L-alanine.
17c
N-[2-(N-tert-Butyloxycarbonyl-O-tert-butyl-L-aspartyl-glycyl)-amino-2-deox
y-.beta.-D-glucopyranosyl]-N-octadecyl-oleamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-oleamide an
d N-tert-butyloxycarbonyl-O-tert-butyl-L-aspartic acid. Yield 88%.
[.alpha.].sub.D =+13.8.degree. (c=0.93, dichloromethane).
17d
N-[2-(N-tert-Butyloxycarbonyl-glycyl-glycyl-glycyl)-amino-2-deoxy-.beta.-D
-glucopyranosyl]-N-octadecyl-oleamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-oleamide an
d N-tert-butyloxycarbonyl-glycyl-glycine. Yield 81%. [.alpha.].sub.D
=+15.0.degree. (c=0.94, dichloromethane).
17e
N-[2-(N-tert-Butyloxycarbonyl-L-alanyl-L-alanyl-glycyl)-amino-2-deoxy-.bet
a.-D-glucopyranosyl]-N-octadecyl-oleamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-oleamide an
d N-tert-butyloxycarbonyl-L-alanyl-L-alanine. Yield 55%. [.alpha.].sub.D
=+10.3.degree. (c=0.85, dichloromethane).
17f
N-[2-(N-tert-Butyloxycarbonyl-glycyl-L-alanyl)-amino-2-deoxy-.beta.-D-gluc
opyranosyl]-N-octadecyl-oleamide.
from
N-(2-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-oleamide
and N-tert-butyloxycarbonyl-glycine.
17g
N-[2-(N-tert-Butyloxycarbonyl-O-tert-butyl-L-aspartyl-L-alanyl)-amino-2-de
oxy-.beta.-D-glucopyranosyl]-N-octadecyl-oleamide.
from
N-(2-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-oleamide
and N-tert-butyloxycarbonyl-O-tert-butyl-L-aspartic acid. Yield 27%.
[.alpha.].sub.D =-1.5.degree. (c=0.55, dichloromethane).
17h
N-[2-(N-tert-Butyloxycarbonyl-glycyl-glycyl-L-alanyl)-amino-2-deoxy-.beta.
-D-glucopyranosyl]-N-octadecyl-oleamide.
from
N-(2-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-oleamide
and N-tert-butyloxycarbonyl-glycyl-glycine. Yield 76%. [.alpha.].sub.D
=+14.9.degree. (c=1.05, dichloromethane).
17i
N-[2-(N-tert-Butyloxycarbonyl-L-alanyl-L-alanyl-L-alanyl)-amino-2-deoxy-.b
eta.-D-glucopyranosyl]-N-octadecyl-oleamide.
from
N-(2-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-oleamide
and N-tert-butyloxycarbonyl-L-alanyl-L-alanine. Yield 75%. [.alpha.].sub.D
=+17.9.degree. (c=0.96, dichloromethane).
17j
N-[2-(di-N-tert-Butyloxycarbonyl-L-lysyl-L-alanyl)-amino-2-deoxy-.beta.-D-
glucopyranosyl]-N-octadecyl-oleamide.
from
N-(2-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-oleamide
and di-N-tert-butyloxycarbonyl-L-lysine. Yield 95%. [.alpha.].sub.D
=-0.12.degree. (c=0.84, dichloromethane).
18a
N-[2-N-Carbobenzoxy-glycyl-glycyl)-amino-2-deoxy-.beta.-D-galactopyranosyl
]-N-dodecyl-octadecanamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-galactopyranosyl)-N-dodecyl-octadecanam
ide and N-carbobenzoxy-glycine.
18b
N-[2-N-Carbobenzoxy-L-alanyl-glycyl)-amino-2-deoxy-.beta.-D-galactopyranos
yl]-N-dodecyl-octadecanamide.
from
N-(2-glycyl-amino-2-deoxy-.beta.-D-galactopyranosyl)-N-dodecyl-octadecanam
ide and N-carbobenzoxy-L-alanine.
Example 2
General procedure for reacting the N-protected 2-aminoacylamino-2-deoxy
compounds, substituted with amino acids, of the formula (I) to give the
N-unsubstituted 6-aminoacylamino-6-deoxy compounds of the formula (I):
The N-carbobenzoxy-protected compound of the general formula (VI) (1.0
mmol) is dissolved in tetrahydrofuran (10 ml), methanol (5 ml) and 1 N
hydrochloric acid (1 ml), and 10% palladium on carbon (0.2 g) is added.
The mixture is hydrogenated in a hydrogen atmosphere under atmospheric
pressure for 16 h. The mixture is subsequently filtered over a Celite
filter bed and the residue is concentrated under reduced pressure. In many
cases crystallization proceeds from methanol (4 ml) and conc. ammonia (0.2
ml). Otherwise, the residue is purified by column chromatography over
silica gel (eluent dichloromethane/methanol/conc. ammonia 10:1:0.1). For
conversion to the corresponding hydrochloride, the residue can be
dissolved in tetrahydrofuran (5 ml), water (30 ml) and 1 N hydrochloric
aid (1.5 ml) and freeze-dried.
General procedure for eliminating the tert-butyloxycarbonyl groups in the
compounds of the formula (I) to give the amines of the formula (I):
The compound of the general formula (VI) (1.0 mmol), substituted with the
tert-butyloxycarbonyl group, is dissolved in dichloromethane (10 ml) at
0.degree., and trifluoroacetic acid (10 ml) is added. After 2 h at
0.degree., the mixture is diluted with toluene (50 ml) and concentrated
under reduced pressure. The residue obtained is taken up three times in
toluene (50 ml each time) and in each case concentrated under reduced
pressure. The residue obtained is purified by column chromatography over
silica gel (gradient dichloromethane-methanol-conc. ammonia
20:1:0.1.fwdarw.10:1:0.1.fwdarw.10:3:0.1). For conversion to the
corresponding hydrochloride, the residue can be dissolved in
tetrahydrofuran (5 ml), water (30 ml) and 1 N hydrochloric acid (1.5 ml)
and freeze-dried.
21a
N-(2-Glycyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-dodecyl-dodeca
namide.
21b
N-(2-L-Alanyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-dodecyl-dode
canamide.
21c
N-(2-L-Phenylalanyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-dodecy
l-dodecanamide.
21d
N-(2-Glycyl-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-dodecyl-dode
canamide.
21e
N-(2-Glycyl-D-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-dodecyl-dode
canamide.
21f
N-(2-L-Aspartyl-D-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-dodecyl-
dodecanamide.
22a
N-(2-Glycyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-dod
ecanamide. Yield 91%. [.alpha.].sub.D =+14.9.degree. (c=0.84,
N,N-dimethylformamide), m.p. 163.degree. (decomposition).
22b
N-(2-Sarcosyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-d
odecanamide. Yield 68%. [.alpha.].sub.D =+16.1.degree. (c=0.93,
N,N-dimethylformamide), m.p. 116.degree..
22c
N-(2-L-Alanyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-d
odecanamide. Yield 90%. [.alpha.].sub.D =+18.7.degree. (c=0.97,
N,N-dimethylformamide), m.p. 115-117.degree..
22d
N-(2-L-Valyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-do
decanamide. Yield 90%. [.alpha.].sub.D =+44.7.degree. (c=0.96,
N,N-dimethylformamide), m.p. 120.degree. (decomposition).
22e
N-(2-L-Seryl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-do
decanamide. Yield 68%. [.alpha.].sub.D =+11.3.degree. (c=0.98,
N,N-dimethylformamide), m.p. 141-143.degree..
22f
N-(2-L-Glutamyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl
-dodecanamide.
22g
N-(2-L-Glutaminyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradec
yl-dodecanamide.
22h
N-(2-L-Glycyl-glycyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetra
decyl-dodecanamide. Yield 78%. [.alpha.].sub.D =+17.1.degree. (c=0.92,
N,N-dimethylformamide), m.p. 177-178.degree..
22i
N-(2-Glycyl-glycyl-glycyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-
tetradecyl-dodecanamide.
22j
N-(2-Alanyl-glycyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetrade
cyl-dodecanamide.
22k
N-(2-L-Alanyl-L-alanyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tet
radecyl-dodecanamide. Yield 80%. [.alpha.].sub.D =+21.1.degree. (c=0.90,
N,N-dimethylformamide), m.p. 132-134.degree..
23a
N-(2-Glycyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-dode
canamide.
23b
N-(2-L-Valyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-dod
ecanamide.
23c
N-(2-L-Leucyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-octadecyl-dode
canamide.
23d
N-(2-L-Glutamyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-
dodecanamide.
23e
N-(2-L-Glutaminyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecy
l-dodecanamide.
23f
N-(2-L-Arginyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-d
odecanamide.
24a
N-(2-Glycyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-oct
adecanamide.
24b
N-(2-Glycyl-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-o
ctadecanamide.
24c
N-(2-L-Leucyl-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl
-octadecanamide.
24d
N-(2-L-Alanyl-L-leucyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl
-octadecanamide.
24e
N-(2-L-Leucyl-L-leucyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl
-octadecanamide.
25a
N-(2-Glycyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-octa
decanamide.
25b
N-(2-L-Alanyl-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-
octadecanamide.
25c
N-(2-D-Alanyl-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-
octadecanamide.
25d
N-(2-D-Alanyl-D-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-
octadecanamide.
25e
N-(2-D-Alanyl-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-
octadecanamide.
25f
N-(2-L-Lysyl-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-o
ctadecanamide.
26a
N-(2-Glycyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-ole
amide. Yield: 96%. [.alpha.].sub.D =+13.2.degree. (c=0.86,
tetrahydrofuran).
26b
N-(2-L-Alanyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-o
leamide. Yield: 97%. [.alpha.].sub.D =+29.6.degree. (c=0.90,
tetrahydrofuran).
26c
N-(2-Glycyl-glycyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetrade
cyl-oleamide. Yield: 86%. [.alpha.].sub.D =+13.1.degree. (c=0.94,
tetrahydrofuran).
26d
N-(2-L-Alanyl-L-alanyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tet
radecyl-oleamide. Yield: 97%. [.alpha.].sub.D =+19.9.degree. (c=0.87,
tetrahydrofuran).
26e
N-(2-Glycyl-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-o
leamide. Yield: 97%. [.alpha.].sub.D =-6.6.degree. (c=1.05,
tetrahydrofuran).
26f
N-(2-L-Alanyl-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl
-oleamide. Yield: 98%. [.alpha.].sub.D =+7.1.degree. (c=0.87,
tetrahydrofuran).
26g
N-(2-L-Leucyl-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl
-oleamide. Yield: 96%. [.alpha.].sub.D =-1.6.degree. (c=0.88,
tetrahydrofuran).
26h
N-(2-Glycyl-glycyl-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetra
decyl-oleamide. Yield: 96%. [.alpha.].sub.D =+8.1.degree. (c=0.97,
tetrahydrofuran).
26i
N-(2-Glycyl-L-leucyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl-o
leamide. Yield: 97%. [.alpha.].sub.D =-9.1.degree. (c=1.02,
tetrahydrofuran).
26j
N-(2-L-Alanyl-L-leucyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetradecyl
-oleamide. Yield: 87%. [.alpha.].sub.D =+1.0.degree. (c=0.74,
tetrahydrofuran).
26k
N-(2-Glycyl-glycyl-L-leucyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-tetra
decyl-oleamide. Yield: 95%. [.alpha.].sub.D =-2.9.degree. (c=0.87,
tetrahydrofuran).
27a
N-(2-Glycyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-olea
mide.
27b
N-(2-L-Alanyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-ol
eamide.
27c
N-(2-L-Aspartyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-
oleamide. Yield 92%. [.alpha.].sub.D =+11.3.degree. (c=0.90,
N,N-dimethylformamide).
27d
N-(2-Glycyl-glycyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadec
yl-oleamide. Yield 94%. [.alpha.].sub.D =+12.5.degree. (c=0.93, methanol).
27e
N-(2-L-Alanyl-L-alanyl-glycyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-oct
adecyl-oleamide. Yield 91%. [.alpha.].sub.D =+14.3.degree. (c=0.92,
methanol).
27f
N-(2-Glycyl-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-ol
eamide.
27g
N-(2-L-Aspartyl-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecy
l-oleamide. Yield 88%. [.alpha.].sub.D =+35.6.degree. (c=0.76,
dichloromethane).
27h
N-(2-L-Glycyl-glycyl-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-oct
adecyl-oleamide. Yield 96%. [.alpha.].sub.D =-57.1.degree. (c=0.77,
dichloromethane).
27i
N-(2-L-Alanyl-L-alanyl-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-o
ctadecyl-oleamide. Yield 85%. [.alpha.].sub.D =+7.4.degree. (c=0.82,
dichloromethane).
27j
N-(2-L-Lysyl-L-alanyl-amino-2-deoxy-.beta.-D-glucopyranosyl)-N-octadecyl-o
leamide. Yield 84%. [.alpha.].sub.D =+4.6.degree. (c=1.09, methanol).
28a
N-(2-Glycyl-glycyl-amino-2-deoxy-.beta.-D-galactopyranosyl)-N-dodecyl-octa
decanamide.
28b
N-(2-L-Alanyl-glycyl-amino-2-deoxy-.beta.-D-galactopyranosyl)-N-dodecyl-oc
tadecanamide.
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